The worldwide incidence of obesity has risen dramatically in recent years. In the U.S., one third of adults are obese and two thirds are overweight. The excessive increase in body weight in the population is a major public health concern owing to its contribution to a diverse array of medical conditions including metabolic syndrome, insulin resistance, type 2 diabetes, dyslipidemia, cardiovascular disease and non-alcoholic fatty liver disease. There are few pharmacological therapies to treat or provide protection against the development of obesity.
Current treatment for obesity includes combinations of the following: diet, exercise, behavior modification, weightloss drugs and in extreme cases, gastrointestinal surgery. Of the few medications that are available to treat obesity, phentermine is approved only for short term use, sibutramine is approved for longer term use but may cause an increase in blood pressure and orlistat, which blocks the absorption of dietary fat, has unpleasant side effects (greasy stool).
The Maf1 protein is an essential mediator of transcriptional repression by RNA polymerase III in budding yeast. The protein resides at the downstream end of multiple nutrient and stress signaling pathways that control cell growth by coordinately regulating ribosome and tRNA synthesis. Maf1 functions to integrate the responses from these diverse pathways to balance the synthesis of tRNAs, 5S rRNA and other small non-coding RNAs with the needs of the cell. Maf1 is post-translationally regulated and interacts directly with components of the RNA polymerase III transcription machinery.
Maf1 orthologs are found in all eukaryotes and the regulatory function of the protein, as determined in yeast, is conserved in human cells. Human Maf1 is ubiquitously expressed and like its yeast counterpart, is required for maximal repression of RNA polymerase III transcription following inhibition of TOR signaling (e.g. by rapamycin) or in response to genotoxic stress. The phospho-regulation of Maf1 and its interactions with components of the RNA polymerase III transcription machinery are also conserved between yeast and humans. In contrast to yeast, the repressive function of Maf1 in mammals is not limited to the RNA polymerase III system but affects all three nuclear RNA polymerases. Studies in glioblastoma cells have shown that Maf1 directly regulates a subset of RNA polymerase II promoters, including the gene encoding the TATA box-binding protein TBP. By altering the cellular concentration of TBP, Maf1 indirectly affects the transcription of ribosomal RNA genes by RNA polymerase I and may indirectly affect the expression of other genes whose transcription by RNA polymerase II is limited by TBP.
The current invention addresses the need for a pharmacological therapy to treat or prevent obesity and/or obesity related diseases.